Phosphordiamidite compounds such as cyanoalkyl tetraalkylphosphordiamidite compounds are key reagents for the preparation of antisense drugs. Typically, such intermediate compounds are prepared by a two-step reaction in which a phosphorus trihalide is reacted with a 2-cyanoalkanol or 2-cyanoalkoxytrialkylsilane to form 2-cyanoalkylphosphordihalidite (NC—R1—O—P—X2 wherein R1 is an alkyl group preferably having from 1 to 6 carbon atoms and X is a halide). The resulting phosphordihalidite compound is reacted with a dialkylamine to give the desired product (cyanoalkyl tetraalkylphosphordiamidite) having the following formula NC—R1—O—P[N(R2)]2 wherein each of R1 and R is an alkyl group, preferably having from 1 to 6 carbon atoms. An amine hydrohalide is produced as a byproduct. A major portion of the amine hydrohalide can be removed by filtration but there always remains a small amount of amine hydrohalide dissolved in the reaction media which can adversely affect the storage stability of the cyanoalkyl tetraalkylphosphordiamidite compounds. In particular, the presence of the amine hydrohalide renders the desired product unstable at ambient temperatures over extended periods of time.
It would therefore be a significant advance in the art to provide a method for the production of phosphordiamidites and particularly cyanoalkyl tetraalkylphosphordiamidites in which amine hydrohalide byproducts are removed from the reaction system to the extent that the desired product is stable at ambient temperatures for up to extended periods of time.